Methods for treating trichotillomania

ABSTRACT

Methods for treating trichotillomania by local administration of a Clostridial toxin. The local administration can be by intramuscular, transdermal, intradermal or subdermal administration of a low dose of  botulinum  toxin.

BACKGROUND

[0001] The present invention relates to methods for treating certainobsessive compulsive disorders. In particular, the present inventionincludes methods for treating various repetitive and/or injurious motoractivity symptoms of certain obsessive compulsive disorders byperipheral administration of a Clostridial toxin.

[0002] Obsessions are persistent ideas, thoughts, impulses or mentalimages that cause distress and anxiety. Obsessions can involve themes ofaggression, contamination, sex or somatic concerns. Compulsions arerepetitive, stereotyped motor acts an individual feels required toperform to reduce anxiety or distress. The compulsion usually can beresisted only temporarily, with resistance followed by an increasingsense of unease and tension. The mounting tension is released only byperforming the irrational motor act or ritual. Compulsions very incomplexity from simple actions such as touching, lip licking, tappingand rubbing to complex behaviors such as repetitive hand washing, hairpulling and body rocking. Additionally, compulsive behaviors can includehoarding, repeating, checking (i.e. repeated checking that a door islocked), counting (i.e. compulsive counting of footsteps) and arrangingbehaviors, as well as various self-injurious behaviors, such asself-biting (i.e. finger biting), head banging, eye poking, skinpicking, skin cutting, skin burning, eye enucleation and castration.Unfortunates with such disturbing self-injurious compulsions mustfrequently be restrained or fitted with suitable restraints (such as amouth guard) to prevent further injury to themselves. These compulsionscan be severely disabling and can accompany psychosis, intoxication,Tourette's syndrome and mental retardation.

[0003] Thus, obsessive compulsive disorders can combine both obsessivethoughts and compulsive behaviors, and can be defined as a chroniccondition characterized by recurrent intrusive thoughts and ritualisticbehaviors that consume much of the afflicted person's attention andactivity, thereby impairing everyday functioning. The behaviors of anobsessive and/or compulsive disorder typically begin in late childhoodor early adulthood and the patient experiences marked tension anddistress upon resisting the obsessions and compulsions. Epidemiologicdata indicates a lifetime prevalence of 2 to 3 percent worldwide andobsessive compulsive disorders are more common in males and in firstborn children. See e.g. page 2490 of Fauci, A. S. et al., editors,Harrison's Principles of Internal Medicine, McGraw Hill, fourteenthedition (1998).

[0004] Functional neuroimaging (i.e. positron emission tomography)studies, brain lesion analysis, and the results of neurosurgicalintervention to treat obsessive compulsive disorders indicate thatdysfunction within particular basal ganglia and ventral prefrontalcortical structures provides a proposed pathophysiology for obsessivecompulsive disorders. See e.g. pages 963-964 of Zigmond, M. J. et al,editors, Fundamental Neuroscience, Academic Press (1999).

[0005] Clearly, obsessive compulsive disorders can cause greatembarrassment, distress and anguish to both the cognizant patient soafflicted as well as to his or her caregiver.

[0006] Tourette's Syndrome

[0007] Tourette's syndrome is usually characterized by multiple motortics and one or more vocal tics. The tics can appear simultaneously orat different periods during the illness. The tics can occur many times aday, and recurrently throughout a period of more than one year. Duringthis period, there is almost never a tic-free period of more than a fewconsecutive months. Those afflicted with Tourette's syndrome sufferdisturbances which can comprise complex tics and cause marked distressor significant impairment in social, occupational, and other importantareas of functioning. The onset of the disorder is typically before theage of eighteen. The complex tics of Tourette's syndrome are not due tothe direct physiological effects of a substance (e.g., stimulants) or ageneral medical condition (e.g., Huntington's disease or postviralencephalitis) and are thought to be a part of the Tourette's diseaseprocess. The anatomical location, number, frequency, complexity, andseverity of the tics often change over time. The tics typically involvethe head and, frequently, other parts of the body, such as the torso andupper and lower limbs. The vocal tics include various words or soundssuch as clicks, grunts, yelps, barks, sniffs, snorts, and coughs.Coprolalia (a complex vocal tic involving the uttering of obscenities),is present in a few individuals (less than 10%) with this disorder.Complex motor tics involving touching, squatting, deep knee bends,retracing steps, and twirling when walking may be present. Inapproximately one-half the individuals with this disorder. The firstsymptoms to appear are often bouts of a single tic, most frequently eyeblinking, less frequently tics involving another part of the face or thebody. Initial symptoms can also include tongue protrusion, squatting,sniffing, hopping, skipping, throat clearing, stuttering, utteringsounds or words, and coprolalia.

[0008] Whereas the repetitive motor activities symptomatic of Tourette'ssyndrome can be characterized as true tics (that is, as habitual,repeated contraction of certain muscles, as in throat clearing,sniffing, lip pursing or excessive blinking) they are an isolated anddistinct subset of behaviors distinct from obsessive compulsivedisorders, as defined by the Diagnostic and Statistical Manual of theAmerican Psychiatric Association (the “DSM-IVR”, fourth revisededition). There are a number of obsessive and/or compulsive disorderswhich involve more complex non tic repetitive motor activity, frequentlyinjurious, as can occur in dermatillomania, trichotillomania, handwashing, head banging, eye poking, body rocking, finger biting,counting, and checking disorders.

[0009] Dermatillomania (Compulsive Skin Picking)

[0010] The primary characteristic of compulsive skin picking is therepetitive picking at one's own skin to the extent of causing damage.Usually, but not always, the face is the primary location for skinpicking. However compulsive skin picking, also known as dermatillomaniaor neurotic excoriation, can involve any part of the body. Individualswith compulsive skin picking may pick at normal skin variations such asfreckles and moles, at actual pre-existing scabs, sores or acneblemishes, or at imagined skin defects that nobody else can observe. Thecompulsive skin picking patient may use his or her fingernails, as wellas their teeth, tweezers, pins or other mechanical devices. As a result,dermatillomania can cause bleeding, bruises, infections, and/orpermanent disfigurement of the skin.

[0011] Sometimes skin-picking is preceded by a high level of tension anda strong itch or urge to pick. Likewise, carrying out the skin-pickingcan be followed by a feeling of relief or pleasure. A compulsive skinpicking episode can be a conscious response to anxiety or depression,but is frequently done as an unconscious habit. Individuals withcompulsive skin picking often attempt to camouflage the damage caused totheir skin by using make-up or wearing clothes to cover the subsequentmarks and scars. In extreme cases, individuals with compulsive skinpicking avoid social situations in an effort to prevent others fromseeing the scars, scabs, and bruises that result from skin picking.

[0012] The primary treatment modality for compulsive skin pickingdepends on the level of awareness the individual has regarding theproblem. If the compulsive skin picking is generally an unconscioushabit, the primary treatment is a form of cognitive-behavioral therapycalled habit reversal training (HRT). HRT is based on the principle thatskin-picking is a conditioned response to specific situations andevents, and that the individual with compulsive skin picking isfrequently unaware of these triggers. HRT challenges the problem in atwo-fold process. First, the individual with compulsive skin pickinglearns how to become more consciously aware of situations and eventsthat trigger skin-picking episodes. Second, the individual learns toutilize alternative behaviors in response to these situations andevents. Unfortunately HRT does not have a high success rate. If thepatient is unaware of or not fully cognizant of his compulsive skinpicking, pharmacologic therapy is recommended. Significant side effectshave occurred from the current drug therapy.

[0013] Trichotillomania (Compulsive Hair Pulling)

[0014] Trichotillomania (TTM) is an compulsive disorder where thepatient pulls out his or her hair from the scalp, eyelashes, eyebrows,or other parts of the body, resulting in noticeable bald patches. Thussymptoms of trichotillomania includes recurrent pulling out of one'shair resulting in noticeable hair loss, and this is usually preceded byan increasing sense of tension immediately before pulling out the hairor when resisting the behavior, followed by pleasure, gratification, orrelief while the hair is being pulled out. This disorder can causesignificant distress and impairment in social, occupational, or otherimportant areas of functioning. It is estimated that trichotillomaniaaffects one to two percent of the population, or four to eleven millionAmericans. TTM seems to strike most frequently in the pre-or earlyadolescent years. The typical first-time hair puller is 12 years old,although TTM has affected people as young as one and as old as seventy.About ninety percent of those with TTM are women.

[0015] Although the symptoms range greatly in severity, location on thebody, and response to treatment, most people with TTM pull enough hairover a long enough period of time that they have bald spots on theirheads (or missing eyelashes, eyebrows, pubic, or underarm hair), whichthey go to great lengths to cover with hairstyles, scarves or clothing,or makeup. The persistence of the compulsion can vary considerably, attimes, the urge may be so strong that it makes thinking of anything elsenearly impossible.

[0016] Treatments for TTM include behavioral therapy and drugs. Inbehavioral therapy, patients learn a structured method of keeping trackof the symptoms and associated behaviors, increasing awareness ofpulling, substituting incompatible behaviors and several othertechniques aimed at reversing the “habit” of pulling. Althoughmedications clearly help some people temporarily, symptoms are likely toreturn when the medication is stopped unless behavioral therapy isincorporated into treatment. Medications may help to reduce thedepression and any obsessive-compulsive symptoms the person may beexperiencing. Commonly used medications include fluoxetine (Prozac),fluvoxamine (Luvox), sertraline (Zoloft), paroxetine (Paxil),clomipramine (Anafranil), valproate (Depakote), and lithium carbonate(Lithobid, Eskalith). Unfortunately, behavioral therapies have limitedsuccess, and the drugs therapies can have significant side effects andrequire regular, chronic repeat dosings.

[0017] Thus, there are many drawbacks and deficiencies with currentobsessive compulsive disorder therapies. Treatment regimes availableinclude chronic administration of drugs which inhibit serotonin reuptake(such drugs are called SSRIs or serotonin reuptake inhibitors) andbehavior modification therapies. Clomipramine, fluoxetine andfluvoxamine are approved for the treatment of obsessive compulsivedisorders. Notably, clomipramine is a tricyclic antidepressant which ispoorly tolerated due to significant anticholinergic and sedative sideeffects. Additionally, fluoxetine and fluvoxamine (SSRIs) also have aside affect profile, which can include cardiac arrhythmias, althoughthey tend to be more benign that clomipramine. Furthermore, only about50 to 60 percent of patients with an obsessive compulsive disorder showan acceptable degree of improvement when either or bothpharmacotherapies, and behavior modification strategies have been tried.

[0018]Botulinum Toxin

[0019] The genus Clostridium has more than one hundred and twenty sevenspecies, grouped according to their morphology and functions. Theanaerobic, gram positive bacterium Clostridium botulinum produces apotent polypeptide neurotoxin, botulinum toxin, which causes aneuroparalytic illness in humans and animals referred to as botulism.The spores of Clostridium botulinum are found in soil and can grow inimproperly sterilized and sealed food containers of home basedcanneries, which are the cause of many of the cases of botulism. Theeffects of botulism typically appear 18 to 36 hours after eating thefoodstuffs infected with a Clostridium botulinum culture or spores. Thebotulinum toxin can apparently pass unattenuated through the lining ofthe gut and attack peripheral motor neurons. Symptoms of botulinum toxinintoxication can progress from difficulty walking, swallowing, andspeaking to paralysis of the respiratory muscles and death.

[0020]Botulinum toxin type A is the most lethal natural biological agentknown to man. About 50 picograms of a commercially available botulinumtoxin type A (purified neurotoxin complex)¹ is a LD₅₀ in mice (i.e. 1unit). One unit of BOTOX® contains about 50 picograms (about 56attomoles) of botulinum toxin type A complex. Interestingly, on a molarbasis, botulinum toxin type A is about 1.8 billion times more lethalthan diphtheria, about 600 million times more lethal than sodiumcyanide, about 30 million times more lethal than cobra toxin and about12 million times more lethal than cholera. Singh, Critical Aspects ofBacterial Protein Toxins, pages 63-84 (chapter 4) of Natural Toxins II,edited by B. R. Singh et al., Plenum Press, New York (1976) (where thestated LD₅₀ of botulinum toxin type A of 0.3 ng equals 1 U is correctedfor the fact that about 0.05 ng of BOTOX® equals 1 unit). One unit (U)of botulinum toxin is defined as the LD₅₀ upon intraperitoneal injectioninto female Swiss Webster mice weighing 18 to 20 grams each.

[0021] Seven generally immunologically distinct botulinum neurotoxinshave been characterized, these being respectively botulinum neurotoxinserotypes A, B, C₁, D, E, F and G each of which is distinguished byneutralization with type-specific antibodies. The different serotypes ofbotulinum toxin vary in the animal species that they affect and in theseverity and duration of the paralysis they evoke. For example, it hasbeen determined that botulinum toxin type A is 500 times more potent, asmeasured by the rate of paralysis produced in the rat, than is botulinumtoxin type B. Additionally, botulinum toxin type B has been determinedto be non-toxic in primates at a dose of 480 U/kg which is about 12times the primate LD₅₀ for botulinum toxin type A. Moyer E et al.,Botulinum Toxin Type B: Experimental and Clinical Experience, beingchapter 6, pages 71-85 of “Therapy With Botulinum Toxin”, edited byJankovic, J. et al. (1994), Marcel Dekker, Inc. Botulinum toxinapparently binds with high affinity to cholinergic motor neurons, istranslocated into the neuron and blocks the release of acetylcholine.Additional uptake can take place through low affinity receptors, as wellas by phagocytosis and pinocytosis.

[0022] Regardless of serotype, the molecular mechanism of toxinintoxication appears to be similar and to involve at least three stepsor stages. In the first step of the process, the toxin binds to thepresynaptic membrane of the target neuron through a specific interactionbetween the heavy chain, H chain, and a cell surface receptor; thereceptor is thought to be different for each type of botulinum toxin andfor tetanus toxin. The carboxyl end segment of the H chain, H_(C),appears to be important for targeting of the toxin to the cell surface.

[0023] In the second step, the toxin crosses the plasma membrane of thepoisoned cell. The toxin is first engulfed by the cell throughreceptor-mediated endocytosis, and an endosome containing the toxin isformed. The toxin then escapes the endosome into the cytoplasm of thecell. This step is thought to be mediated by the amino end segment ofthe H chain, H_(N), which triggers a conformational change of the toxinin response to a pH of about 5.5 or lower. Endosomes are known topossess a proton pump which decreases intra-endosomal pH. Theconformational shift exposes hydrophobic residues in the toxin, whichpermits the toxin to embed itself in the endosomal membrane. The toxin(or at a minimum the light chain) then translocates through theendosomal membrane into the cytoplasm.

[0024] The last step of the mechanism of botulinum toxin activityappears to involve reduction of the disulfide bond joining the heavychain, H chain, and the light chain, L chain. The entire toxic activityof botulinum and tetanus toxins is contained in the L chain of theholotoxin; the L chain is a zinc (Zn++) endopeptidase which selectivelycleaves proteins essential for recognition and docking ofneurotransmitter-containing vesicles with the cytoplasmic surface of theplasma membrane, and fusion of the vesicles with the plasma membrane.Tetanus neurotoxin, botulinum toxin types B, D, F, and G causedegradation of synaptobrevin (also called vesicle-associated membraneprotein (VAMP)), a synaptosomal membrane protein. Most of the VAMPpresent at the cytoplasmic surface of the synaptic vesicle is removed asa result of any one of these cleavage events. Botulinum toxin serotype Aand E cleave SNAP-25. Botulinum toxin serotype C₁ was originally thoughtto cleave syntaxin, but was found to cleave syntaxin and SNAP-25. Eachof the botulinum toxins specifically cleaves a different bond, exceptbotulinum toxin type B (and tetanus toxin) which cleave the same bond.Each of these cleavages block the process of vesicle-membrane docking,thereby preventing exocytosis of vesicle content.

[0025]Botulinum toxins have been used in clinical settings for thetreatment of neuromuscular disorders characterized by hyperactiveskeletal muscles (i.e. motor disorders). In 1989 a botulinum toxin typeA complex has been approved by the U.S. Food and Drug Administration forthe treatment of blepharospasm, strabismus and hemifacial spasm.Subsequently, a botulinum toxin type A was also approved by the FDA forthe treatment of cervical dystonia and for the treatment of glabellarlines, and a botulinum toxin type B was approved for the treatment ofcervical dystonia. Non-type A botulinum toxin serotypes apparently havea lower potency and/or a shorter duration of activity as compared tobotulinum toxin type A. Clinical effects of peripheral intramuscularbotulinum toxin type A are usually seen within one week of injection.The typical duration of symptomatic relief from a single intramuscularinjection of botulinum toxin type A averages about three months,although significantly longer periods of therapeutic activity have beenreported.

[0026] Although all the botulinum toxins serotypes apparently inhibitrelease of the neurotransmitter acetylcholine at the neuromuscularjunction, they do so by affecting different neurosecretory proteinsand/or cleaving these proteins at different sites. For example,botulinum types A and E both cleave the 25 kiloDalton (kD) synaptosomalassociated protein (SNAP-25), but they target different amino acidsequences within this protein. Botulinum toxin types B, D, F and G acton vesicle-associated protein (VAMP, also called synaptobrevin), witheach serotype cleaving the protein at a different site. Finally,botulinum toxin type C₁ has been shown to cleave both syntaxin andSNAP-25. These differences in mechanism of action may affect therelative potency and/or duration of action of the various botulinumtoxin serotypes. Apparently, a substrate for a botulinum toxin can befound in a variety of different cell types. See e.g. Biochem J 1;339 (pt1):159-65:1999, and Mov Disord, 10(3):376:1995 (pancreatic islet B cellscontains at least SNAP-25 and synaptobrevin).

[0027] The molecular weight of the botulinum toxin protein molecule, forall seven of the known botulinum toxin serotypes, is about 150 kD.Interestingly, the botulinum toxins are released by Clostridialbacterium as complexes comprising the 150 kD botulinum toxin proteinmolecule along with associated non-toxin proteins. Thus, the botulinumtoxin type A complex can be produced by Clostridial bacterium as 900 kD,500 kD and 300 kD forms. Botulinum toxin types B and C₁ is apparentlyproduced as only a 700 kD or 500 kD complex. Botulinum toxin type D isproduced as both 300 kD and 500 kD complexes. Finally, botulinum toxintypes E and F are produced as only approximately 300 kD complexes. Thecomplexes (i.e. molecular weight greater than about 150 kD) are believedto contain a non-toxin hemaglutinin protein and a non-toxin andnon-toxic nonhemaglutinin protein. These two non-toxin proteins (whichalong with the botulinum toxin molecule comprise the relevant neurotoxincomplex) may act to provide stability against denaturation to thebotulinum toxin molecule and protection against digestive acids whentoxin is ingested. Additionally, it is possible that the larger (greaterthan about 150 kD molecular weight) botulinum toxin complexes may resultin a slower rate of diffusion of the botulinum toxin away from a site ofintramuscular injection of a botulinum toxin complex.

[0028] In vitro studies have indicated that botulinum toxin inhibitspotassium cation induced release of both acetylcholine andnorepinephrine from primary cell cultures of brainstem tissue.Additionally, it has been reported that botulinum toxin inhibits theevoked release of both glycine and glutamate in primary cultures ofspinal cord neurons and that in brain synaptosome preparations botulinumtoxin inhibits the release of each of the neurotransmittersacetylcholine, dopamine, norepinephrine (Habermann E., et al., TetanusToxin and Botulinum A and C Neurotoxins Inhibit Noradrenaline ReleaseFrom Cultured Mouse Brain, J Neurochem 51(2);522-527:1988) CGRP,substance P and glutamate (Sanchez-Prieto, J., et al., Botulinum Toxin ABlocks Glutamate Exocytosis From Guinea Pig Cerebral CorticalSynaptosomes, Eur J. Biochem 165;675-681:1897. Thus, when adequateconcentrations are used, stimulus-evoked release of mostneurotransmitters is blocked by botulinum toxin. See e.g. Pearce, L. B.,Pharmacologic Characterization of Botulinum Toxin For Basic Science andMedicine, Toxicon 35(9);1373-1412 at 1393; Bigalke H., et al., BotulinumA Neurotoxin Inhibits Non-Cholinergic Synaptic Transmission in MouseSpinal Cord Neurons in Culture, Brain Research 360;318-324:1985;Habermann E., Inhibition by Tetanus and Botulinum A Toxin of the releaseof [ ³ H]Noradrenaline and [ ³ H]GABA From Rat Brain Homogenate,Experientia 44;224-226:1988, Bigalke H., et al., Tetanus Toxin andBotulinum A Toxin Inhibit Release and Uptake of Various Transmitters, asStudied with Particulate Preparations From Rat Brain and Spinal Cord,Naunyn-Schmiedeberg's Arch Pharmacol 316;244-251:1981, and; Jankovic J.et al., Therapy With Botulinum Toxin, Marcel Dekker, Inc., (1994), page5.

[0029]Botulinum toxin type A can be obtained by establishing and growingcultures of Clostridium botulinum in a fermenter and then harvesting andpurifying the fermented mixture in accordance with known procedures. Allthe botulinum toxin serotypes are initially synthesized as inactivesingle chain proteins which must be cleaved or nicked by proteases tobecome neuroactive. The bacterial strains that make botulinum toxinserotypes A and G possess endogenous proteases and serotypes A and G cantherefore be recovered from bacterial cultures in predominantly theiractive form. In contrast, botulinum toxin serotypes C₁, D and E aresynthesized by nonproteolytic strains and are therefore typicallyunactivated when recovered from culture. Serotypes B and F are producedby both proteolytic and nonproteolytic strains and therefore can berecovered in either the active or inactive form. However, even theproteolytic strains that produce, for example, the botulinum toxin typeB serotype only cleave a portion of the toxin produced. The exactproportion of nicked to unnicked molecules depends on the length ofincubation and the temperature of the culture. Therefore, a certainpercentage of any preparation of, for example, the botulinum toxin typeB toxin is likely to be inactive, possibly accounting for the knownsignificantly lower potency of botulinum toxin type B as compared tobotulinum toxin type A. The presence of inactive botulinum toxinmolecules in a clinical preparation will contribute to the overallprotein load of the preparation, which has been linked to increasedantigenicity, without contributing to its clinical efficacy.Additionally, it is known that botulinum toxin type B has, uponintramuscular injection, a shorter duration of activity and is also lesspotent than botulinum toxin type A at the same dose level.

[0030] High quality crystalline botulinum toxin type A can be producedfrom the Hall A strain of Clostridium botulinum with characteristics of≧3×10⁷ U/mg, an A₂₆₀/A₂₇₈ of less than 0.60 and a distinct pattern ofbanding on gel electrophoresis. The known Shantz process can be used toobtain crystalline botulinum toxin type A, as set forth in Shantz, E.J., et al, Properties and use of Botulinum toxin and Other MicrobialNeurotoxins in Medicine, Microbiol Rev. 56;80-99:1992. Generally, thebotulinum toxin type A complex can be isolated and purified from ananaerobic fermentation by cultivating Clostridium botulinum type A in asuitable medium. The known process can also be used, upon separation outof the non-toxin proteins, to obtain pure botulinum toxins, such as forexample: purified botulinum toxin type A with an approximately 150 kDmolecular weight with a specific potency of 1-2×10⁸ LD₅₀ U/mg orgreater; purified botulinum toxin type B with an approximately 156 kDmolecular weight with a specific potency of 1-2×10⁸ LD₅₀ U/mg orgreater, and; purified botulinum toxin type F with an approximately 155kD molecular weight with a specific potency of 1-2×10⁷ LD₅₀ U/mg orgreater.

[0031]Botulinum toxins and/or botulinum toxin complexes can be obtainedfrom List Biological Laboratories, Inc., Campbell, Calif.; the Centrefor Applied Microbiology and Research, Porton Down, U.K.; Wako (Osaka,Japan), Metabiologics (Madison, Wis.) as well as from Sigma Chemicals ofSt Louis, Mo. Pure botulinum toxin can also be used to prepare apharmaceutical composition.

[0032] As with enzymes generally, the biological activities of thebotulinum toxins (which are intracellular peptidases) is dependant, atleast in part, upon their three dimensional conformation. Thus,botulinum toxin type A is detoxified by heat, various chemicals surfacestretching and surface drying. Additionally, it is known that dilutionof the toxin complex obtained by the known culturing, fermentation andpurification to the much, much lower toxin concentrations used forpharmaceutical composition formulation results in rapid detoxificationof the toxin unless a suitable stabilizing agent is present. Dilution ofthe toxin from milligram quantities to a solution containing nanogramsper milliliter presents significant difficulties because of the rapidloss of specific toxicity upon such great dilution. Since the toxin maybe used months or years after the toxin containing pharmaceuticalcomposition is formulated, the toxin can stabilized with a stabilizingagent such as albumin and gelatin.

[0033] A commercially available botulinum toxin containingpharmaceutical composition is sold under the trademark BOTOX® (availablefrom Allergan, Inc., of Irvine, Calif.). BOTOX® consists of a purifiedbotulinum toxin type A complex, albumin and sodium chloride packaged insterile, vacuum-dried form. The botulinum toxin type A is made from aculture of the Hall strain of Clostridium botulinum grown in a mediumcontaining N-Z amine and yeast extract. The botulinum toxin type Acomplex is purified from the culture solution by a series of acidprecipitations to a crystalline complex consisting of the active highmolecular weight toxin protein and an associated hemagglutinin protein.The crystalline complex is re-dissolved in a solution containing salineand albumin and sterile filtered (0.2 microns) prior to vacuum-drying.The vacuum-dried product is stored in a freezer at or below −5° C.BOTOX® can be reconstituted with sterile, non-preserved saline prior tointramuscular injection. Each vial of BOTOX® contains about 100 units(U) of Clostridium botulinum toxin type A purified neurotoxin complex,0.5 milligrams of human serum albumin and 0.9 milligrams of sodiumchloride in a sterile, vacuum-dried form without a preservative.

[0034] To reconstitute vacuum-dried BOTOX®, sterile normal salinewithout a preservative; (0.9% Sodium Chloride Injection) is used bydrawing up the proper amount of diluent in the appropriate size syringe.Since BOTOX® may be denatured by bubbling or similar violent agitation,the diluent is gently injected into the vial. For sterility reasonsBOTOX® is preferably administered within four hours after the vial isremoved from the freezer and reconstituted. During these four hours,reconstituted BOTOX® can be stored in a refrigerator at about 2° C. toabout 8° C. Reconstituted, refrigerated BOTOX® has been reported toretain its potency for at least about two weeks. Neurology,48:249-53:1997.

[0035] It has been reported that botulinum toxin type A has been used in10 clinical settings as follows:

[0036] (1) about 75-125 units of BOTOX® per intramuscular injection(multiple muscles) to treat cervical dystonia;

[0037] (2) 5-10 units of BOTOX® per intramuscular injection to treatglabellar lines (brow furrows) (5 units injected intramuscularly intothe procerus muscle and 10 units injected intramuscularly into eachcorrugator supercilii muscle);

[0038] (3) about 30-80 units of BOTOX® to treat constipation byintrasphincter injection of the puborectalis muscle;

[0039] (4) about 1-5 units per muscle of intramuscularly injected BOTOX®to treat blepharospasm by injecting the lateral pre-tarsal orbicularisoculi muscle of the upper lid and the lateral pre-tarsal orbicularisoculi of the lower lid.

[0040] (5) to treat strabismus, extraocular muscles have been injectedintramuscularly with between about 1-5 units of BOTOX®, the amountinjected varying based upon both the size of the muscle to be injectedand the extent of muscle paralysis desired (i.e. amount of dioptercorrection desired).

[0041] (6) to treat upper limb spasticity following stroke byintramuscular injections of BOTOX® into five different upper limb flexormuscles, as follows:

[0042] (a) flexor digitorum profundus: 7.5 U to 30 U

[0043] (b) flexor digitorum sublimus: 7.5 U to 30 U

[0044] (c) flexor carpi ulnaris: 10 U to 40 U

[0045] (d) flexor carpi radialis: 15 U to 60 U

[0046] (e) biceps brachii: 50 U to 200 U. Each of the five indicatedmuscles has been injected at the same treatment session, so that thepatient receives from 90 U to 360 U of upper limb flexor muscle BOTOX®by intramuscular injection at each treatment session.

[0047] (7) to treat migraine, pericranial injected (injectedsymmetrically into glabellar, frontalis and temporalis muscles)injection of 25 U of BOTOX® has showed significant benefit as aprophylactic treatment of migraine compared to vehicle as measured bydecreased measures of migraine frequency, maximal severity, associatedvomiting and acute medication use over the three month period followingthe 25 U injection.

[0048] Additionally, intramuscular botulinum toxin has been used in thetreatment of tremor in patients with Parkinson's disease, although ithas been reported that results have not been impressive. Marjama-Jyons,J., et al., Tremor-Predominant Parkinson's Disease, Drugs & Aging16(4);273-278:2000.

[0049] It is known that botulinum toxin type A can have an efficacy forup to 12 months (European J. Neurology 6 (Supp 4): S111-S1150:1999), andin some circumstances for as long as 27 months. The Laryngoscope109:1344-1346:1999. However, the usual duration of an intramuscularinjection of Botox® is typically about 3 to 4 months.

[0050] The success of botulinum toxin type A to treat a variety ofclinical conditions has led to interest in other botulinum toxinserotypes. Two commercially available botulinum type A preparations foruse in humans are BOTOX® available from Allergan, Inc., of Irvine,Calif., and Dysport® available from Beaufour Ipsen, Porton Down,England. A Botulinum toxin type B preparation (MyoBloc®) is availablefrom Elan Pharmaceuticals of San Francisco, Calif.

[0051] In addition to having pharmacologic actions at the peripherallocation, botulinum toxins may also have inhibitory effects in thecentral nervous system. Work by Weigand et al, Nauny-Schmiedeberg'sArch. Pharmacol. 1976; 292, 161-165, and Habermann, Nauny-Schmiedeberg'sArch. Pharmacol. 1974; 281, 47-56 showed that botulinum toxin is able toascend to the spinal area by retrograde transport. As such, a botulinumtoxin injected at a peripheral location, for example intramuscularly,may be retrograde transported to the spinal cord.

[0052] U.S. Pat. No. 5,989,545 discloses that a modified clostridialneurotoxin or fragment thereof, preferably a botulinum toxin, chemicallyconjugated or recombinantly fused to a particular targeting moiety canbe used to treat pain by administration of the agent to the spinal cord.

[0053] A botulinum toxin has also been proposed for the treatment ofrhinorrhea, hyperhydrosis and other disorders mediated by the autonomicnervous system (U.S. Pat. No. 5,766,605), tension headache, U.S. Pat.No. 6,458,365), migraine headache (U.S. Pat. No. 5,714,468),post-operative pain and visceral pain (U.S. Pat. No. 6,464,986), paintreatment by intraspinal toxin administration (U.S. Pat. No. 6,113,915),Parkinson's disease and other diseases with a motor disorder component,by intracranial toxin administration (U.S. Pat. No. 6,306,403), hairgrowth and hair retention (U.S. Pat. No. 6,299,893), psoriasis anddermatitis (U.S. Pat. No. 5,670,484), injured muscles (U.S. Pat. No.6,423,319, various cancers (U.S. Pat. No. 6,139,845), pancreaticdisorders (U.S. Pat. No. 6,143,306), smooth muscle disorders (U.S. Pat.No. 5,437,291, including injection of a botulinum toxin into the upperand lower esophageal, pyloric and anal sphincters)), prostate disorders(U.S. Pat. No. 6,365,164), inflammation, arthritis and gout (U.S. Pat.No. 6,063,768), juvenile cerebral palsy (U.S. Pat. No. 6,395,277), innerear disorders (U.S. Pat. No. 6,265,379), thyroid disorders (U.S. Pat.No. 6,358,513), parathyroid disorders (U.S. Pat. No. 6,328,977).Additionally, controlled release toxin implants are known (see e.g. U.S.Pat. Nos. 6,306,423 and 6,312,708).

[0054] A botulinum toxin has been used to treat recalcitrant restlessleg syndrome (Kudelko, K. M., et al., Successful treatment ofrecalcitrant Restless Legs Syndrome with botulinum toxin A, Mov Disord2002;17 (Suppl 5):S242). Restless leg syndrome (RLS) involves anuncomfortable sensation in muscles, usually in the legs and thighs thatoccurs most commonly in middle aged woman. The abnormal sensation isrelieved by moving the legs. RLS is not an obsessive compulsive disorderbecause it is not characterized by either recurrent intrusive thoughtsor ritualistic behaviors. The amount of a botulinum toxin administeredto treat restless leg syndrome (i.e. 25-50 units of a type A botulinumtoxin per leg) exceeds the amount of toxin typically used to reduce thetone of a hypertonic or rigid thigh muscle, and can indeed can causesome paralysis of the injected thigh muscle.

[0055] Additionally, the finger biting, lip biting and tongue bitingself mutilation behaviors of Lesch Nyhan syndrome have been treated byinjecting a botulinum toxin into the chewing or clenching muscles of themouth in one patient. Dabrowski E., et al, Botulinum toxin as a noveltreatment for self-mutilation in Lesch-Nyhan syndrome, Ann Neurol 2002September; 52 (3 Supp 1): S1 57. Injection of the fingers, lips ortongue is believed contraindicated because of the ulceration andsensitivity of these extremities due to the injurious behaviors of thesyndrome.

[0056] Furthermore, a botulinum toxin has been used to treat focaldystonic tics or muscle spasms of Tourette's syndrome. Jankovic, J.,Botulinum toxin in the treatment of tics associated with Tourette'ssyndrome, Neurology 1993 April; 43 (4 Supp 2): A310; Jankovic, J.,Botulinum toxin in the treatment of dystonic tics, Mov Disord 1994 May;9(3): 347-9, and; Krauss J., et al., Severe motor tics causing cervicalmyelopathy in Tourette's syndrome, Mov Disord 1996; 11 (5): 563-6. Thesepublications indicate that a botulinum toxin can act to treat aTourette's syndrome tic both by reducing the force of contractionnecessary to generate the muscle movement (i.e. by a partial paralysisof the tic involved muscles) as well as by an inhibition or resolutionof the premonitory symptoms (i.e. by removing the urge to carry out orto accomplish the tic) which precede the tic. Unfortunately, significantneck pain, neck weakness and neck pain was reported in some of theTourette's syndrome patient's administered a botulinum toxin to treat aneck tic. Additionally, the literature is contradictory with regard touse of a botulinum toxin to treat a Tourette's syndrome tic, as othershave reported no relief upon use of botulinum toxin to treat a Tourettesyndrome tic, even at dose levels that caused muscle weakness orparalysis. Chappell, P. B., et al., Future therapies of Tourettesyndrome, Neurol Clin 1997 May; 15(2): 429-50, at 444.

[0057] Tetanus toxin, as well as derivatives (i.e. with a non-nativetargeting moiety), fragments, hybrids and chimeras thereof can also havetherapeutic utility. The tetanus toxin bears many similarities to thebotulinum toxins. Thus, both the tetanus toxin and the botulinum toxinsare polypeptides made by closely related species of Clostridium(Clostridium tetani and Clostridium botulinum, respectively).Additionally, both the tetanus toxin and the botulinum toxins aredichain proteins composed of a light chain (molecular weight about 50kD) covalently bound by a single disulfide bond to a heavy chain(molecular weight about 100 kD). Hence, the molecular weight of tetanustoxin and of each of the seven botulinum toxins (non-complexed) is about150 kD. Furthermore, for both the tetanus toxin and the botulinumtoxins, the light chain bears the domain which exhibits intracellularbiological (protease) activity, while the heavy chain comprises thereceptor binding (immunogenic) and cell membrane translocationaldomains.

[0058] Further, both the tetanus toxin and the botulinum toxins exhibita high, specific affinity for gangliocide receptors on the surface ofpresynaptic cholinergic neurons. Receptor mediated endocytosis oftetanus toxin by peripheral cholinergic neurons results in retrogradeaxonal transport, blocking of the release of inhibitoryneurotransmitters from central synapses and a spastic paralysis.Contrarily, receptor mediated endocytosis of botulinum toxin byperipheral cholinergic neurons results in little if any retrogradetransport, inhibition of acetylcholine exocytosis from the intoxicatedperipheral motor neurons and a flaccid paralysis.

[0059] Finally, the tetanus toxin and the botulinum toxins resemble eachother in both biosynthesis and molecular architecture. Thus, there is anoverall 34% identity between the protein sequences of tetanus toxin andbotulinum toxin type A, and a sequence identity as high as 62% for somefunctional domains. Binz T. et al., The Complete Sequence of BotulinumNeurotoxin Type A and Comparison with Other Clostridial Neurotoxins, JBiological Chemistry 265(16);9153-9158:1990.

[0060] Acetylcholine

[0061] Typically only a single type of small molecule neurotransmitteris released by each type of neuron in the mammalian nervous system,although there is evidence which suggests that several neuromodulatorscan be released by the same neuron. The neurotransmitter acetylcholineis secreted by neurons in many areas of the brain, but specifically bythe large pyramidal cells of the motor cortex, by several differentneurons in the basal ganglia, by the motor neurons that innervate theskeletal muscles, by the preganglionic neurons of the autonomic nervoussystem (both sympathetic and parasympathetic), by the bag 1 fibers ofthe muscle spindle fiber, by the postganglionic neurons of theparasympathetic nervous system, and by some of the postganglionicneurons of the sympathetic nervous system. Essentially, only thepostganglionic sympathetic nerve fibers to the sweat glands, thepiloerector muscles and a few blood vessels are cholinergic as most ofthe postganglionic neurons of the sympathetic nervous system secret theneurotransmitter norepinephine. In most instances acetylcholine has anexcitatory effect. However, acetylcholine is known to have inhibitoryeffects at some of the peripheral parasympathetic nerve endings, such asinhibition of heart rate by the vagal nerve.

[0062] The efferent signals of the autonomic nervous system aretransmitted to the body through either the sympathetic nervous system orthe parasympathetic nervous system. The preganglionic neurons of thesympathetic nervous system extend from preganglionic sympathetic neuroncell bodies located in the intermediolateral horn of the spinal cord.The preganglionic sympathetic nerve fibers, extending from the cellbody, synapse with postganglionic neurons located in either aparavertebral sympathetic ganglion or in a prevertebral ganglion. Since,the preganglionic neurons of both the sympathetic and parasympatheticnervous system are cholinergic, application of acetylcholine to theganglia will excite both sympathetic and parasympathetic postganglionicneurons.

[0063] Acetylcholine activates two types of receptors, muscarinic andnicotinic receptors. The muscarinic receptors are found in all effectorcells stimulated by the postganglionic, neurons of the parasympatheticnervous system as well as in those stimulated by the postganglioniccholinergic neurons of the sympathetic nervous system. The nicotinicreceptors are found in the adrenal medulla, as well as within theautonomic ganglia, that is on the cell surface of the postganglionicneuron at the synapse between the preganglionic and postganglionicneurons of both the sympathetic and parasympathetic systems. Nicotinicreceptors are also found in many nonautonomic nerve endings, for examplein the membranes of skeletal muscle fibers at the neuromuscularjunction.

[0064] Acetylcholine is released from cholinergic neurons when small,clear, intracellular vesicles fuse with the presynaptic neuronal cellmembrane. A wide variety of non-neuronal secretory cells, such as,adrenal medulla (as well as the PC12 cell line) and pancreatic isletcells release catecholamines and parathyroid hormone, respectively, fromlarge dense-core vesicles. The PC12 cell line is a clone of ratpheochromocytoma cells extensively used as a tissue culture model forstudies of sympathoadrenal development. Botulinum toxin inhibits therelease of both types of compounds from both types of cells in vitro,permeabilized (as by electroporation) or by direct injection of thetoxin into the denervated cell. Botulinum toxin is also known to blockrelease of the neurotransmitter glutamate from cortical synaptosomescell cultures.

[0065] A neuromuscular junction is formed in skeletal muscle by theproximity of axons to muscle cells. A signal transmitted through thenervous system results in an action potential at the terminal axon, withactivation of ion channels and resulting release of the neurotransmitteracetylcholine from intraneuronal synaptic vesicles, for example at themotor endplate of the neuromuscular junction. The acetylcholine crossesthe extracellular space to bind with acetylcholine receptor proteins onthe surface of the muscle end plate. Once sufficient binding hasoccurred, an action potential of the muscle cell causes specificmembrane ion channel changes, resulting in muscle cell contraction. Theacetylcholine is then released from the muscle cells and metabolized bycholinesterases in the extracellular space. The metabolites are recycledback into the terminal axon for reprocessing into further acetylcholine.

[0066] What is needed therefore is a non-surgical method for effectivelytreating effectively treating inappropriate, compulsive, ritualisticand/or obsessive behaviors characterized by repetitive, unproductivemotor activity.

SUMMARY

[0067] The present invention meets this need and provides methods foreffectively treating inappropriate, compulsive, ritualistic and/orobsessive behaviors characterized by repetitive, unproductive motoractivity with a low dose of a Clostridial toxin.

[0068] A method according to my invention can be carried out byadministration of a Clostridial toxin to a patient with an obsessivedisorder and/or with a compulsive disorder. As used herein “obsessivecompulsive disorder” means an obsessive disorder or a compulsivedisorder, or a disorder which combines elements of both obsession andcompulsion. “Treating” means to alleviate (or to eliminate) at least onesymptom, either temporarily or permanently. The Clostridial toxin ispreferably a botulinum toxin (as either a complex or as a pure [i.e.about 150 kDa molecule], such as a botulinum toxin A, B, C, D, E, F orG. Administration of the Clostridial toxin can be by a transdermal route(i.e. by application of a Clostridial toxin in a cream, patch or lotionvehicle), subdermal route (i.e. subcutaneous or intramuscular) or by anintradermal route of administration.

[0069] A hypothesized physiological reason for the efficacy of myinvention, as explained in greater detail below, is to reduce, inhibitor eliminate particular sensory input (afferent) from the periphery tothe central nervous system (including to the brain) which sensory inputis believed to precede and to be pivotal to the initiation of arepetitive, unproductive motor activity. Such inappropriate sensoryinput can be attenuated or eliminated by targeting sensory neuronslocated within muscle tissues or that are located in or under the skinwith a low dose of a Clostridial toxin.

[0070] The dose of a Clostridial toxin used according to the presentinvention is much less than the amount of toxin that would be used toparalyze a muscle (and is even less than the amount of the toxin used toreduce a rigid muscle tone), since the intent of a method according tothe present invention is not to paralyze a muscle or to reduce the toneof a rigid muscle, but to reduce an undesirable sensory output fromsensory neurons located in or a muscle or in or under the skin.Additionally, the low dose of the Clostridial toxin is selected with avolume to preferably achieve a toxin distribution to multiple sites ofundesirable afferent sensory signals, such as from spindle fibers orsecretory cells in the skin or subdermally.

[0071] Excluded from the scope of present invention is administration(as by intramuscular injection) of a Clostridial toxin (such as abotulinum toxin) into any neck muscles (such as into the spleniimuscles) of a patient because such a local administration of toxin canresult, particularly in adolescent patients, in poor head orientation(“floppy head”), prolonged neck pain, neck weakness and/or neckstiffness and/or exacerbation of a pre-existing neck or spinal injury(often due to the tic itself). Additionally, the complex neurologicalnature of Tourette's syndrome and the contradictory state of the artwith regard to Tourette's syndrome tics contraindicate use of abotulinum toxin to treat a symptom of Tourette's syndrome. Thus,treatment of focal dystonic neck tics, such as the neck tics associatedwith Tourette's syndrome, is excluded from the scope of the presentinvention, as being better treated by head restraints, behavioralmodification therapy and/or proven pharmacologic agents, such as TCAs orSSRIs.

[0072] Thus, my invention is a pharmacologic method for treatinginappropriate, compulsive, ritualistic and/or obsessive behaviorscharacterized by repetitive, unproductive motor activity, which are notneck tics. My invention can be practised by administering a low dose ofa Clostridial toxin to the muscle or muscle group which appears toinitiates the repetitive, unproductive motor activity (i.e. to treatrepetitive hand washing). Alternately my invention can be practised byadministering a low dose of a Clostridial toxin to intradermal orsubdermal sensory neurons which apparently generate an urge, itch orsensation which precedes the repetitive motor activity (i.e. skinpicking). As explained above, my invention is not suitable for thetreatment for any neck tics (whether motor or vocal), and additionallydoes not encompass treatment of any muscle spasms. “Low dose” means anamount of the Clostridial toxin (such as a botulinum toxin) which issufficient to inhibit a sensory output from a muscle to the CNS, butwhich is insufficient to cause either clinically significant muscleparalysis, weakness or hypotonicity.

[0073] The following definitions also apply herein:

[0074] “About” means approximately or nearly and in the context of anumerical value or range set forth herein means±10% of the numericalvalue or range recited or claimed.

[0075] “Alleviating” means a reduction in the occurrence of thedisorder. Thus, alleviating includes some reduction (so that thedisorder is practised for fewer than, or appears in fewer than, than sixhours out of a twenty-four hour period), significant reduction (so thatthe disorder is practised for fewer than, or appears in fewer than,three hours out of a twenty-four hour period), near total reduction (sothat the disorder is practised for fewer than, or appears in fewer than,one hour out of a twenty-four hour period), and total reduction of thedisorder. An alleviating effect may not appear clinically for between 1to 7 days after administration of a Clostridial toxin to a patient

[0076] “Botulinum toxin” means a botulinum neurotoxin as either puretoxin or complex, and excludes botulinum toxins which are notneurotoxins such as the cytotoxic botulinum toxins C₂ and C₃.

[0077] “Disorder” means an inappropriate, compulsive, ritualistic and/orobsessive behaviors characterized by repetitive, unproductive motoractivity, which are not neck tics. Specific obsessive compulsivedisorders are defined as set forth in the DSM-IVR.

[0078] “Local administration” means peripheral administration (i.e. by asubcutaneous, intramuscular, subdermal or transdermal route) of apharmaceutical agent to or to the vicinity of a muscle or of a subdermallocation of a patient by a non-systemic route. Thus, localadministration excludes systemic (i.e. to the blood circulation system)routes of administration, such as intravenous or oral administration.Peripheral administration means administration to the periphery (i.e. toa location on or within a limb, trunk or head of a patient) as opposedto a visceral or gut (i.e. to the viscera) administration. An example oflocal administration is intramuscular injection of a pharmaceuticalagent to a head or facial muscle or subdermal location of a patient.

[0079] Methods for treating a disorder characteristic by inappropriate,compulsive, ritualistic and/or obsessive behaviors characterized byrepetitive, unproductive motor activity with a low dose of a Clostridialtoxin comprise the step of local administration of Clostridialneurotoxin to a patient. The Clostridial neurotoxin is administered in atherapeutically effective amount to alleviate at least one symptom ofthe disorder.

[0080] A suitable Clostridial neurotoxin may be a neurotoxin made by abacterium, for example, the neurotoxin may be made from a Clostridiumbotulinum, Clostridium butyricum, or Clostridium beratti. In certainembodiments of the invention, the disorders are treated by intramuscularadministration a botulinum toxin to the patient. The botulinum toxin maybe a botulinum toxin type A, type B, type C, type D, type E, type F, ortype G. The effects of the botulinum toxin may persist for between about1 month and 5 years. The botulinum neurotoxin can be a recombinantlymade botulinum neurotoxins, such as botulinum toxins produced by E.coli. In addition or alternatively, the botulinum neurotoxin can be amodified neurotoxin, that is a botulinum neurotoxin which has at leastone of its amino acids deleted, modified or replaced, as compared to anative or the modified botulinum neurotoxin can be a recombinantproduced botulinum neurotoxin or a derivative or fragment thereof.

[0081] The botulinum neurotoxin is administered to a peripheral sitethat is believed to be involved in the disorder being treated. Thebotulinum neurotoxin can be administered to a muscle which appears toinitiate the disorder and can alleviate the symptoms within a few hoursor within a few days after administration.

[0082] A method for treating trichotillomania according to the presentinvention can comprise the step of local administration of a botulinumtoxin to a patient with trichotillomania to thereby alleviate thetrichotillomania. The botulinum toxin can be selected from the groupconsisting of botulinum toxin types A, B, C, D, E, F and G. Botulinumtoxin type A is a preferred botulinum toxin. The botulinum toxin can beadministered in an amount of between about 1 unit and about 2,500 units(for example between about 1-50 units of a botulinum toxin type A orbetween about 50 to 2,500 units of a botulinum toxin type B) and thealleviation of the disorder can persists for between about 1 month andabout 5 years. The local administration of the botulinum toxin can be toan intradermal or to a subdermal location in the head, face or scalp ofa patient. The local administration can be by intramuscular injection.Alternately, the local administration of the botulinum toxin can be to adermal location or to a muscle location from which the patient perceivesthe existence of a premonitory sensation, which leads to the generationof the disorder, to arise.

[0083] A detailed embodiment of my invention can comprise a method fortreating trichotillomania, the method comprising a step of localadministration to a head, face and/or scalp of a patient withtrichotillomania of between about 1 unit and about 1,500 units of abotulinum toxin type A, thereby alleviating the trichotillomania forbetween about 1 month and about 5 years.

DESCRIPTION

[0084] The present invention is based on the discovery that peripheraladministration of a low dose of a Clostridial toxin (such as a botulinumtoxin) can provide effective treatment or relief of inappropriate,compulsive, ritualistic and/or obsessive behaviors characterized byrepetitive, unproductive motor activity. Thus, a botulinum toxin (suchas a botulinum toxin serotype A, B, C₁, D, E, F or G) can be injectedinto a muscle which initiates (or acts to recruit other muscles to) theundesirable repetitive behavior to thereby suppress and treat such anundesirable and/or self injurious motoric behavioral characteristic.Alternately, the botulinum toxin can be administered to an intradermalor subdermal sensory neuron thereby suppress and treat such anundesirable and/or self injurious motoric behavioral characteristic.

[0085] Without wishing to be bound by theory a physiological mechanismcan be proposed for the efficacy of the present invention. It is knownthat muscles have a complex system of innervation and sensory output.Thus, anterior motor neurons located in each segment of the anteriorhorns of the spinal cord gray matter give rise to efferent alpha motorneurons and efferent gamma motor neurons that leave the spinal cord byway of the anterior roots to innervate skeletal (extrafusal) musclefibers. The alpha motor neurons cause contraction of extrafusal skeletalmuscle fibers while the gamma motor neurons innervate the intrafusalfibers of skeletal muscle. As well as excitation by these two type ofefferent anterior motor neuron projections, there are additional,afferent sensory neurons which project from muscle spindle and golgitendon organs and act to transmit information regarding various muscleparameter status to the spinal cord, cerebellum and cerebral cortex.These afferent motor neurons which relay sensory information from themuscle spindle include type Ia and type II sensory afferent neurons. Seee.g. pages 686-688 of Guyton A. C. et al., Textbook of MedicalPhysiology, W. B. Saunders Company 1996, ninth edition.

[0086] Significantly, it has been determined that a botulinum toxin canact to reduce transmission of sensory information from muscle type Iaafferent neurons. Aoki, K., Physiology and pharmacology of therapeuticbotulinum neurotoxins, in Kreyden, O., editor, Hyperhydrosis andbotulinum toxin in dermatology, Basel, Karger; 2002; 30: pages 107-116,at 109-110. And it has been hypothesized that botulinum toxin can have adirect effect upon muscle cell sensory afferents and modify signals fromthese afferents to the central nervous system. See e.g. Brin, M., etal., Botulinum toxin type A: pharmacology, in Mayer N., editor,Spasticity: etiology, evaluation, management and the role of botulinumtoxin, 2002; pages 110-124, at 112-113; Cui, M., et al., Mechanisms ofthe antinociceptive effect of subcutaneous BOTOX®: inhibition ofperipheral and central nociceptive processing, Naunyn Schmiedebergs ArchPharmacol 2002; 365 (supp 2): R17; Aoki, K., et al., Botulinum toxintype A and other botulinum toxin serotypes: a comparative review ofbiochemical and pharmacological actions, Eur J. Neurol 2001: (suppl 5);21-29. Thus, it has been demonstrated that botulinum toxin can cause analtered sensory output from muscle to CNS and brain.

[0087] Importantly, the sensory neurons from which afferent output is tobe inhibited by a method according to the present invention need not belocated on or within a muscle, but can be in an intradermal or subdermallocation.

[0088] It can be postulated that obsessive-compulsive disorders are dueto disinhibition of a central nervous system control process. Thus, adisinhibition reverberatory circuit may exist between the head of thecaudate nucleus and the thalamus and between the thalamus and thefrontorbito neurons which is sensitive to signals arising fromperipheral sensory information afferent from muscle neurons.Administration of a botulinum toxin to a muscles or skin to reducesensory output from the muscle can permit the brain to regain adequateinhibition control of the obsessive-compulsive disorder motor behaviors,by preventing central generation of a premonitory urge to carry out theobsessive-compulsive disorder behavior. Notably, It has been reportedthat local administration of a botulinum toxin to neck muscles canapparently act to reduce generation of the premonitory urge associatedwith some Tourette's syndrome tics. Jankovic, J., Botulinum toxin in thetreatment of tics associated with Tourette's syndrome, Neurology 1993April; 43 (4 Supp 2): A31 0; Jankovic, J., Botulinum toxin in thetreatment of dystonic tics, Mov Disord 1994 May; 9(3): 347-9, and;Krauss J., et al., Severe motor tics causing cervical myelopathy inTourette's syndrome, Mov Disord 1996; 11 (5): 563-6. Additionally, aspreviously discussed relatively high (paralytic effect) thigh muscledoses of a botulinum toxin have been used to treat restless legsyndrome, and injection of botulinum toxin into the chewing muscle hasbeen used to treat the lip, tongue and finger biting behaviors of LeschNyhan syndrome.

[0089] It is my hypothesis that signals transmitted by afferent nerveswhich innervate muscles (i.e. muscle spindle fibers and muscle painfibers) or from sensory structures in the skin or subdermally induce asensory state which contributes in susceptible individuals to thegeneration of obsessive-compulsive disorder behaviors. That is, afferentsignal from muscles or skin structures provide sensory information tothe brain which then leads to the generation of a complex motor outputin susceptible individuals, such as the self mutilation, obsessive handwashing, hair pulling, or other repetitive behaviors ofobsessive-compulsive disorder. Thus, a local administration of a lowdose of a botulinum toxin to muscle spindle fibers, pain fibers or othersensors in or in the vicinity of a muscle can act to alter the neuralsignal afferent output from these muscles to the brain and therebydecreasing neural (to brain) input and inhibit the undesirableobsessive-compulsive disorder behavior by preventing generation of apremonitory urge.

[0090] Important elements of my invention are firstly that is practisedby use of a local administration of low dose of a botulinum toxin. Theselected low dose causes neither muscle paralysis, weakness nor musclehypotonicity. Secondly, the invention is practised by localadministration of the low dose of the botulinum toxin to the muscle orto the muscle group which initiates the undesirable motor behavior. Forexample, with regard to obsessive finger biting the botulinum toxin isadministered to the hand or forearm muscles. With regard to ritualisticchecking and counting behaviors, the botulinum toxin is administered tothe head muscles, such as scalp, forehead or facial muscles on the basisthat such behaviors are initiated by sensory input from such muscle.

[0091] Conditions treatable by the present invention include skinpicking, hair pulling, head banging, body rocking, counting, checking,and hoarding behaviors which are inappropriate, compulsive, ritualisticand/or obsessive behaviors characterized by repetitive, unproductivemotor activity, which are not neck tics.

[0092] In compulsive skin picking there is often a psychotic sensationof skin crawling with the common description of perception of movementhypodermally. This sensation may very well be due to premonitory urgestriggered by skin associated tiny muscle structures such as the arrectorpili muscles of hair follicles, smooth muscle vasculature of the dermisor neural sensory structures within the skin. Thus, hypodermal(subcutaneous) injection into the dermis of a Clostridial toxin can beexpected to focally relieve or block this sensation for several months.

[0093] Other disorders treatable by a method within the scope of thepresent invention include conditions with stereotypic movements such asDowns Syndrome, pervasive developmental disorder, developmental movementdisorder, autism (hand/finger movement subtype), Asperger's Syndrome(hand/finger movement type) and Rhett's Syndrome (handwashingmovements).

[0094] The administration of the Clostridial toxin is carried out so asto target, for example, focal motoric movements of obsessive compulsivedisorders. Thus, for repetitive hand washing behavior the toxin can beinjected into the forearm muscles associated with washing movements, orinto the hands based upon a pattern for the treatment of hyperhydrosisor a combination thereof. Treatment sites and doses can be selectedbased upon the muscles which initiate the observed movement at doseswhich do not produce significant muscle weakness. Thus, an injectionpattern is selected to focus on the muscles which initiate the observedinappropriate movements.

[0095] The amount of the Clostridial toxin administered according to amethod within the scope of the disclosed invention can vary according tothe particular disorder being treated, its severity and other variouspatient variables including size, weight, age, and responsiveness totherapy. To guide the practitioner, typically, no less than about 1 unitand no more than about 25 units of a botulinum toxin type A (such asBOTOX®) is administered per injection site, per patent treatmentsession. For a botulinum toxin type A such as DYSPORT®, no less thanabout 2 units and no more about 125 units of the botulinum toxin type A10 are administered per injection site, per patent treatment session.For a botulinum toxin type B such as MYOBLOC®, no less than about 40units and no more about 1500 units of the botulinum toxin type B areadministered per injection site, per patent treatment session. Less thanabout 1, 2 or 40 units (of BOTOX®, DYSPORT® and MYOBLOC® respectively)can fail to achieve a desired therapeutic effect, while more than about25, 125 or 1500 units (of BOTOX®, DYSPORT® and MYOBLOC® respectively)can result in significant muscle hypotonicity, weakness and/orparalysis, all of which are undesirable outcomes in a practise of thedisclosed invention because the purpose of my invention is to treatinappropriate compulsive, ritualistic and/or obsessive behaviorscharacterized by repetitive, unproductive motor activity, which are notneck tics, with a low dose of a Clostridial toxin to the muscle ormuscle group which appears to initiates the repetitive, unproductivemotor activity, the dose being sufficient to inhibit a sensory outputfrom a muscle to the CNS, but insufficient to cause either significantmuscle paralysis, weakness or hypotonicity.

[0096] More preferably: for BOTOX® no less than about 2 units and nomore about 20 units of a botulinum toxin type A; for DYSPORT® no lessthan about 4 units and no more than about 100 units, and; for MYOBLOC®,no less than about 80 units and no more than about 1000 units are,respectively, administered per injection site, per patent treatmentsession.

[0097] Most preferably: for BOTOX® 8 no less than about 5 units and nomore about 15 units of a botulinum toxin type A; for DYSPORT® no lessthan about 20 units and no more than about 75 units, and; for MYOBLOC®,no less than about 200 units and no more than about 750 units are,respectively, administered per injection site, per patent treatmentsession. It is important to note that there can be multiple injectionsites (i.e. a pattern of injections) for each patient treatment session.

[0098] Although examples of routes of administration and dosages areprovided, the appropriate route of administration and dosage aregenerally determined on a case by case basis by the attending physician.Such determinations are routine to one of ordinary skill in the art (seefor example, Harrison's Principles of Internal Medicine (1998), editedby Anthony Fauci et al., 14^(th) edition, published by McGraw Hill). Forexample, the route and dosage for administration of a neurotoxinaccording to the present disclosed invention can be selected based uponcriteria such as the solubility characteristics of the neurotoxin chosenas well as the intensity of the disorder as perceived by the patient.

[0099] The present invention is based on the discovery that peripheraladministration of a Clostridial toxin can provide significant and longlasting relief from a variety of different obsessive-compulsivedisorders. Peripheral administration permits a Clostridial toxin to belocally administered at a site, at or near a patient's muscle that has adirect effect on the neurons involved in the disorders,

[0100] The Clostridial toxins used in accordance with the inventiondisclosed herein can inhibit transmission of chemical or electricalsignals between select neuronal groups that are involved in generationof an obsessive-compulsive disorder. The Clostridial toxins preferablyare not cytotoxic to the cells that are exposed to the Clostridialtoxin. The Clostridial toxin can inhibit neurotransmission by reducingor preventing exocytosis of neurotransmitter from the neurons exposed tothe Clostridial toxin. Or, the applied Clostridial toxins may reduceneurotransmission by inhibiting the generation of action potentials ofthe neurons exposed to the toxin. The suppressive effects provided bythe Clostridial toxin should persist for a relatively long period oftime, for example, for more than two months, and potentially for severalyears.

[0101] Examples of Clostridial toxins within the scope of the presentinvention include neurotoxins made by Clostridium botulinum, Clostridiumbutyricum and Clostridium beratti species. In addition, the botulinumtoxins used in the methods of the invention may be a botulinum toxinselected from a group of botulinum toxin types A, B, C, D, E, F, and G.In one embodiment of the invention, the botulinum neurotoxinadministered to the patient is botulinum toxin type A. Botulinum toxintype A is desirable due to its high potency in humans, readyavailability, and known use for the treatment of skeletal and smoothmuscle disorders when locally administered by intramuscular injection.The present invention also includes the use of (a) Clostridialneurotoxins obtained or processed by bacterial culturing, toxinextraction, concentration, preservation, freeze drying, and/orreconstitution; and/or (b) modified or recombinant neurotoxins, that isneurotoxins that have had one or more amino acids or amino acidsequences deliberately deleted, modified or replaced by knownchemical/biochemical amino acid modification procedures or by use ofknown host cell/recombinant vector recombinant technologies, as well asderivatives or fragments of neurotoxins so made. These neurotoxinvariants retain the ability to inhibit neurotransmission between oramong neurons, and some of these variants may provide increaseddurations of inhibitory effects as compared to native neurotoxins, ormay provide enhanced binding specificity to the neurons exposed to theneurotoxins. These neurotoxin variants may be selected by screening thevariants using conventional assays to identify neurotoxins that have thedesired physiological effects of inhibiting neurotransmission.

[0102]Botulinum toxins for use according to the present invention can bestored in lyophilized, vacuum dried form in containers under vacuumpressure or as stable liquids. Prior to lyophilization the botulinumtoxin can be combined with pharmaceutically acceptable excipients,stabilizers and/or carriers, such as albumin. The lyophilized materialcan be reconstituted with saline or water to create a solution orcomposition containing the botulinum toxin to be administered to thepatient.

[0103] Although the composition may only contain a single type ofneurotoxin, such as botulinum toxin type A, as the active ingredient tosuppress neurotransmission, other therapeutic compositions may includetwo or more types of neurotoxins, which may provide enhanced therapeuticeffects of the disorders. For example, a composition administered to apatient may include botulinum toxin type A and botulinum toxin type B.Administering a single composition containing two different neurotoxinsmay permit the effective concentration of each of the neurotoxins to belower than if a single neurotoxin is administered to the patient whilestill achieving the desired therapeutic effects. The compositionadministered to the patient may also contain other pharmaceuticallyactive ingredients, such as, protein receptor or ion channel modulators,in combination with the neurotoxin or neurotoxins. These modulators maycontribute to the reduction in neurotransmission between the variousneurons. For example, a composition may contain gamma aminobutyric acid(GABA) type A receptor modulators that enhance the inhibitory effectsmediated by the GABA_(A) receptor. The GABA_(A) receptor inhibitsneuronal activity by effectively shunting current flow across the cellmembrane. GABA_(A) receptor modulators may enhance the inhibitoryeffects of the GABA_(A) receptor and reduce electrical or chemicalsignal transmission from the neurons. Examples of GABA_(A) receptormodulators include benzodiazepines, such as diazepam, oxaxepam,lorazepam, prazepam, alprazolam, halazeapam, chordiazepoxide, andchlorazepate. Compositions may also contain glutamate receptormodulators that decrease the excitatory effects mediated by glutamatereceptors. Examples of glutamate receptor modulators include agents thatinhibit current flux through AMPA, NMDA, and/or kainate types ofglutamate receptors. The compositions may also include agents thatmodulate dopamine receptors, such as antipsychotics, norepinephrinereceptors, and/or serotonin receptors. The compositions may also includeagents that affect ion flux through voltage gated calcium channels,potassium channels, and/or sodium channels. Thus, the compositions usedto treat obsessive compulsive disorders may include one or moreneurotoxins, such as botulinum toxins, in addition to ion channelreceptor modulators that may reduce neurotransmission.

[0104] The neurotoxin may be administered by any suitable method asdetermined by the attending physician. The methods of administrationpermit the neurotoxin to be administered locally to a selected targettissue. Methods of administration include injection of a solution orcomposition containing the neurotoxin, as described above, and includeimplantation of a controlled release system that controllably releasesthe neurotoxin to the target tissue. Such controlled release systemsreduce the need for repeat injections. Diffusion of biological activityof a botulinum toxin within a tissue appears to be a function of doseand can be graduated. Jankovic J., et al Therapy With Botulinum Toxin,Marcel Dekker, Inc., (1994), page 150. Thus, diffusion of botulinumtoxin can be controlled to reduce potentially undesirable side effectsthat may affect the patient's cognitive abilities. For example, theneurotoxin may be administered so that the neurotoxin primarily effectsneural systems believed to be involved in the obsessive compulsivedisorder, and does not have negatively adverse effects on other neuralsystems.

[0105] A polyanhydride polymer, Gliadel® (Stolle R & D, Inc.,Cincinnati, Ohio) a copolymer of poly-carboxyphenoxypropane and sebacicacid in a ratio 10 of 20:80 has been used to make implants, and has beenintracranially implanted to treat malignant gliomas. Polymer and BCNUcan be co-dissolved in methylene chloride and spray-dried intomicrospheres. The microspheres can then be pressed into discs 1.4 cm indiameter and 1.0 mm thick by compression molding, packaged in aluminumfoil pouches under nitrogen atmosphere and sterilized by 2.2 megaRads ofgamma irradiation. The polymer permits release of carmustine over a 2-3week period, although it can take more than a year for the polymer to belargely degraded. Brem, H., et al, Placebo-Controlled Trial of Safetyand Efficacy of Intraoperative Controlled Delivery by BiodegradablePolymers of Chemotherapy for Recurrent Gliomas, Lancet 345;1008-1012:1995.

[0106] Implants useful in practicing the methods disclosed herein may beprepared by mixing a desired amount of a stabilized neurotoxin (such asnon-reconstituted BOTOX®) into a solution of a suitable polymerdissolved in methylene chloride. The solution may be prepared at roomtemperature. The solution can then be transferred to a Petri dish andthe methylene chloride evaporated in a vacuum desiccator. Depending uponthe implant size desired and hence the amount of incorporatedneurotoxin, a suitable amount of the dried neurotoxin incorporatingimplant is compressed at about 8000 p.s.i. for 5 seconds or at 3000p.s.i. for 17 seconds in a mold to form implant discs encapsulating theneurotoxin. See e.g. Fung L. K. et al., Pharmacokinetics of InterstitialDelivery of Carmustine 4-Hydroperoxycyclophosphamide and Paclitaxel Froma Biodegradable Polymer Implant in the Monkey Brain, Cancer Research58;672-684:1998.

[0107] Local administration of a Clostridial toxin, such as a botulinumtoxin, can provide a high, local therapeutic level of the toxin. Acontrolled release polymer capable of long term, local delivery of aClostridial toxin to a target muscle permits effective dosing of atarget tissue. A suitable implant, as set forth in U.S. Pat. No.6,306,423 entitled “Neurotoxin Implant”, allows the direct introductionof a chemotherapeutic agent to a target tissue via a controlled releasepolymer. The implant polymers used are preferably hydrophobic so as toprotect the polymer incorporated neurotoxin from water induceddecomposition until the toxin is released into the target tissueenvironment.

[0108] Local administration of a botulinum toxin, according to thepresent invention, by injection or implant to a target tissue provides asuperior alternative to systemic administration of pharmaceuticals topatients to alleviate the symptoms associated with the disorderstreated.

[0109] The amount of a Clostridial toxin selected for localadministration to a target tissue according to the present disclosedinvention can be varied based upon criteria such as the disorder beingtreated, its severity, the extent of muscle tissue to be treated,solubility characteristics of the neurotoxin toxin chosen as well as theage, sex, weight and health of the patient. For example, the extent ofthe area of muscle tissue influenced is believed to be proportional tothe volume of neurotoxin injected, while the quantity of the suppressanteffect is, for most dose ranges, believed to be proportional to theconcentration of a Clostridial toxin administered. Methods fordetermining the appropriate route of administration and dosage aregenerally determined on a case by case basis by the attending physician.Such determinations are routine to one of ordinary skill in the art (seefor example, Harrison's Principles of Internal Medicine (1998), editedby Anthony Fauci et al., 14^(th) edition, published by McGraw Hill).

[0110] Significantly, a method within the scope of the present inventioncan provide improved patient function. “Improved patient function” canbe defined as an improvement measured by factors such as a reduced pain,reduced time spent in bed, increased ambulation, healthier attitude,more varied lifestyle and/or healing permitted by normal muscle tone.Improved patient function is synonymous with an improved quality of life(QOL). QOL can be assessed using, for example, the known SF-12 or SF-36health survey scoring procedures. SF-36 assesses a patient's physicaland mental health in the eight domains of physical functioning, rolelimitations due to physical problems, social functioning, bodily pain,general mental health, role limitations due to emotional problems,vitality, and general health perceptions. Scores obtained can becompared to published values available for various general and patientpopulations.

EXAMPLES

[0111] The following non-limiting examples provide those of ordinaryskill in the art with specific preferred methods to treat conditionswithin the scope of the present invention and are not intended to limitthe scope of the invention. In the following examples various modes ofnon-systemic administration of a Clostridial neurotoxin can be carriedout. For example, by intramuscular injection, subcutaneous injection orby implantation of a controlled release implant.

Example 1 Botulinum Toxin Type a Therapy for Head Banging

[0112] A 15 year old male bangs his head on walls and on his school deskwithout obvious triggers. He reports 20-25 head banging episodes a day.Upon examination he relates that he is lonely and feels an urge to, andgratification upon, carrying out the chronic head banging. His foreheadis bruised and tender to the touch. The patient is treated byintramuscular injection of 5 units of a botulinum toxin type A (i.e.BOTOX®) into the forehead muscles bilaterally at two different locations(10 units toxin total). Within 1-7 days after toxin administration thepatient report that he now banging his head only once or twice a day andsuch an alleviation of his condition persists for 4-6 months. Forextended therapeutic relief (1 to 5 years), one or more polymericimplants incorporating a suitable quantity of a botulinum toxin type Acan be placed at the target tissue site.

[0113] A botulinum toxin type B, C, D, E, F or G can be substituted forthe botulinum toxin type A used above, for example by use of 250 unitsof a botulinum toxin type B.

Example 2 Botulinum Toxin Type a Therapy for Repetitive Hand Washing

[0114] A 46 year old male presents with red, chapped hands. He relatescompulsive washing of his hands for 6 to 8 hours a day, often afternormal hygiene activities. The patient is treated by intramuscularinjection of 5 units of a botulinum toxin type A (i.e. BOTOX®) into theforearm muscles bilaterally at two different locations (10 units toxin,per arm). Within 1-7 days after toxin administration the patient reportthat he is washing his hands now for less than one hour a day andalleviation of his condition persists for 4-6 months. For extendedtherapeutic relief (1 to 5 years), one or more polymeric implantsincorporating a suitable quantity of a botulinum toxin type A can beplaced at the target tissue site.

Example 3 Botulinum Toxin Type B Therapy for Repetitive Hand Washing

[0115] A 22 year old female presents with red, chapped hands. Sherelates compulsive washing of hers hands for 7 to 9 hours a day, oftenafter 10 normal hygiene activities. She relates perception in her handsof an urge to wash them. The patient is treated by intramuscularinjection of 225 units of a botulinum toxin type B (i.e. MYOBLOC®) intothe palm of each of her hands. Within 1-7 days after toxinadministration the patient report that she is washing her hands now forless than one half hour a day and alleviation of the condition persistsfor 4-6 months. For extended therapeutic relief (1 to 5 years), one ormore polymeric implants incorporating a suitable quantity of a botulinumtoxin type B can be placed at the target tissue site.

[0116] A botulinum toxin type C, D, E, F or G can be substituted for thebotulinum toxin type A or B used in the examples above.

Example 4 Botulinum Toxin Therapy for Trichotillomania

[0117] A sixteen year old girl with normal intelligence is referred byher dermatologist and examined for several, irregular bald patches onher head. The hair loss is on the contralateral side of the dominanthand and the affected areas include broken hairs of varying lengths withskin discoloration secondary to rubbing the scalp. The child admits topulling her hair because “I'm depressed.” Adrenal function is normal andtrichotillomania is diagnosed. The patient's trichotillomania showednominal response to antidepressant medication, including tricyclicantidepressants (desipramine and imipramine), as these medicationsresulted in a brief 2-3 day remission of the hair pulling. Othertherapeutic interventions included cognitive behavioral therapy andcounseling, both of which were unsuccessful, despite attendance. Thechild is treated by intramuscular injection of 5 units of a botulinumtoxin type A (i.e. BOTOX®) into the frontalis and occipitalis muscles(10 units toxin, per treatment session). Alternately, so as to achieve awider distribution of the botulinum toxin, 100 units of a botulinumtoxin type A in 5 ml of saline can be injected into multiple (about 20sites) scalp locations. Within 1-7 days after toxin administration thepatient report that she has stopped pulling her hair and alleviation ofher condition persists for 4-6 months. For extended therapeutic relief(1 to 5 years), one or more polymeric implants incorporating a suitablequantity of a botulinum toxin type A can be placed at the target tissuesite.

[0118] A botulinum toxin type B, C, D, E, F or G can be substituted forthe botulinum toxin type A used above, for example by use of 250 unitsof a botulinum toxin type B.

Example 5 Botulinum Toxin Type a Therapy for Dermatillomania

[0119] A 57 year old married woman is examined for chronic skin pickingover the last 3 years to her arms and legs, never leaving the lesionsalone long enough to heal. Prior to clinical presentation she has triedalternative treatment approaches for the picking, including acupuncture,dermatology consultation, and group therapy. She picked with herfingernails and often ingests the scabs after removal. She relates andurge which builds up and which is relieved by the picking. Her conditionis recalcitrant to behavior modification therapy, fluoxetine andvenlafaxine. After informed consent, 4 units of a botulinum toxin type A(i.e. BOTOX®) are injected subdermally at the locations of the chronicskin picking. Alternately, so as to achieve a wider distribution of thebotulinum toxin, 100 units of a botulinum toxin type A in 5 ml of salinecan be injected into multiple (about 20) sites of the skin picking.Within 1-7 days after toxin administration the patient has stoppedpicking her skin and alleviation of her condition persists for 4-6months. For extended therapeutic relief (1 to 5 years), one or morepolymeric implants incorporating a suitable quantity of a botulinumtoxin type A can be placed at the target tissue site.

Example 6 Botulinum Toxin Type B Therapy for Dermatillomania

[0120] A 26 year old, divorced, college educated man seeks treatment forhis chronic, self injurious skin picking. He describes an awareness ofclogged pores on his face, especially around his nose and chin which heties to unclog with his fingernails. The target of his skin pickingincludes “raised skin” as well as healthy skin. Skin picking episodesend when his skin becomes inflamed or bleeding. He reports about 20 skinpicking episodes every day, with each episode lasting 1 to five minutes.He relates feeling tension or nervousness build up before the skinpicking and relief after he has picked. 200 units of a botulinum toxintype B is are injected subdermally at three separate the locations ofthe chronic facial skin picking. Alternately, so as to achieve a widerdistribution of the botulinum toxin, 5000 units of a botulinum toxintype B in 5 ml of saline can be injected into multiple (about 20) sitesof the skin picking. Within 1-7 days after toxin administration thepatient has stopped picking his skin and alleviation of the conditionpersists for 4-6 months. For extended therapeutic relief (1 to 5 years),one or more polymeric implants incorporating a suitable quantity of abotulinum toxin type B can be placed at the target tissue site.

[0121] A botulinum toxin type C, D, E, F or G can be substituted for thebotulinum toxin type A or B used in the examples above.

Example 7 Botulinum Toxin Type a Therapy for Finger Biting

[0122] An eight year old boy with mild mental retardation bites hisfingers hands regularly and his fingers have become ulcerated. He motherreports that he will bite his fingers continuously unless restrained.The patient is treated by intramuscular injection of 3 units of abotulinum toxin type A (i.e. BOTOX®) into the base of each finger oneach hand. Alternately, the forearm muscles can be injected bilaterallywith 10 units of the botulinum toxin. Within 1-7 days after toxinadministration the finger biting has completely subsided and resolved.His fingers heal and this alleviation of his condition persists for 4-6months. For extended therapeutic relief (1 to 5 years), one or morepolymeric implants incorporating a suitable quantity of a botulinumtoxin type A can be placed at the target tissue site.

[0123] A botulinum toxin type B, C, D, E, F or G can be substituted forthe botulinum toxin type A used above, for example by use of 250 unitsof a botulinum toxin type B.

Example 8 Botulinum Toxin Type a Therapy for Pruritis Associated withPsychosis

[0124] A 26 year old married female is referred for pharmacologicallyrecalcitrant skin itching which is described to feel as if an insect iscrawling under her skin. On repeated instances when not restrained shehas cut herself to “let out the bugs”. Auditory and visualhallucinations are also present. The patient is treated 4 units of abotulinum toxin type A (i.e. BOTOX®) are injected subdermally at thelocations of the chronic skin itching. Alternately, so as to achieve awider distribution of the botulinum toxin, 100 units of a botulinumtoxin type A in 5 ml of saline can be injected into multiple (about 20)sites of the perceived skin itching. Within 1-7 days after toxinadministration the patient reports relief from the skin itching andalleviation of her condition persists for 4-6 months. For extendedtherapeutic relief (1 to 5 years), one or more polymeric implantsincorporating a suitable quantity of a botulinum toxin type A can beplaced at the target tissue site.

[0125] Although the present invention has been described in detail withregard to certain preferred methods, other embodiments, versions, andmodifications within the scope of the present invention are possible.For example, a wide variety of neurotoxins can be effectively used inthe methods of the present invention. Additionally, the presentinvention includes peripheral administration methods to alleviate adisorder wherein two or more neurotoxins, such as two or more botulinumtoxins, are administered concurrently or consecutively. For example,botulinum toxin type A can be administered until a loss of clinicalresponse or neutralizing antibodies develop, followed by administrationof botulinum toxin type B. Alternately, a combination of any two or moreof the botulinum serotypes A-G can be locally administered to controlthe onset and duration of the desired therapeutic result. Furthermore,non-neurotoxin compounds can be administered prior to, concurrently withor subsequent to administration of the neurotoxin to proved adjuncteffect such as enhanced or a more rapid onset of denervation before theneurotoxin, such as a botulinum toxin, begins to exert its therapeuticeffect.

[0126] A method for treating a disorder according to the inventiondisclosed herein has many benefits and advantages, including thefollowing:

[0127] 1. the symptoms can be dramatically reduced.

[0128] 2. the symptoms of an obsessive-compulsive disorder can bereduced for from about two to about six months per injection ofneurotoxin and for from about one year to about five years upon use of acontrolled release neurotoxin implant.

[0129] 3. the injected or implanted neurotoxin exerts an intramusculartarget tissue site specific suppression of neuronal activity.

[0130] 4. the injected or implanted Clostridial neurotoxin shows littleor no tendency to diffuse or to be transported away from theintramuscular (or intradermal or subdermal) injection or implantationsite.

[0131] 5. few or no significant undesirable side effects occur fromintramuscular (or intradermal or subdermal) injection or implantation ofthe Clostridial neurotoxin.

[0132] 6. the suppressant effects of the present methods can result inthe desirable side effects of greater patient mobility, a more positiveattitude, and an improved quality of life.

[0133] Although the present invention has been described in detail withregard to certain preferred methods, other embodiments, versions, andmodifications within the scope of the present invention are possible.For example, a wide variety of neurotoxins can be effectively used inthe methods of the present invention. Additionally, the presentinvention includes local administration methods wherein two or moreClostridial neurotoxins, such as two or more botulinum toxins, areadministered concurrently or consecutively. For example, botulinum toxintype A can be locally administered until a loss of clinical response orneutralizing antibodies develop, followed by administration of botulinumtoxin type B. Furthermore, non-neurotoxin compounds can be locallyadministered prior to, concurrently with or subsequent to administrationof the neurotoxin to provide adjunct effect such as enhanced or a morerapid onset of suppression before the neurotoxin, such as a botulinumtoxin, begins to exert its more long lasting suppressant effect.

[0134] My invention also includes within its scope the use of aneurotoxin, such as a botulinum toxin, in the preparation of amedicament for the treatment of an obsessive-compulsive disorder, bylocal administration of the Clostridial neurotoxin.

[0135] All references, articles, patents, applications and publicationsset forth above are incorporated herein by reference in theirentireties.

[0136] Accordingly, the spirit and scope of the following claims shouldnot be limited to the descriptions of the preferred embodiments setforth above.

1. A method for treating trichotillomania, the method comprising a stepof local administration of a botulinum toxin to a patient withtrichotillomania, thereby alleviating the trichotillomania of saidpatient.
 2. The method of claim 1, wherein the botulinum toxin isselected from the group consisting of botulinum toxin types A, B, C, D,E, F and G.
 3. The method of claim 1, wherein the botulinum toxin is abotulinum toxin type A.
 4. The method of claim 1, wherein the botulinumtoxin is administered in an amount of between about 1 unit and about1,500 units.
 5. The method of claim 1, wherein the alleviation persistsfor between about 1 month and about 5 years.
 6. The method of claim 1,wherein the local administration of the botulinum toxin is to a headmuscle.
 7. The method of claim 1, wherein the local administration ofthe botulinum toxin is to a facial muscle.
 8. The method of claim 1,wherein the local administration is by intramuscular injection.
 9. Themethod of claim 1, wherein the local administration of the botulinumtoxin is to a dermal location or to a muscle location from which thepatient perceives the existence of a premonitory sensation, which leadsto the generation of the disorder, to arise.
 10. A method for treatingtrichotillomania, the method comprising a step of local administrationto a head muscle of a patient with trichotillomania of between about 1unit and about 1,500 units of a botulinum toxin type A, therebyalleviating trichotillomania of said patient for between about 1 monthand about 5 years.
 11. A method for treating a human patient withtrichotillomania, the method comprising a step of local administrationof a botulinum toxin to a head muscle of the patient withtrichotillomania, thereby alleviating the trichotillomania of saidpatient, wherein the botulinum toxin is selected from the groupconsisting of botulinum toxin types A, B, C, D, E, F, G and combinationsthereof.
 12. The method of claim 11, wherein the botulinum toxin isbotulinum toxin type A.
 13. The method of claim 11, wherein thebotulinum toxin is administered in an amount of between about 1 unit andabout 1,500 units.
 14. The method of claim 11, wherein the alleviationpersists for between about 1 month and about 5 years.
 15. The method ofclaim 11, wherein the local administration is by intramuscularinjection.
 16. A method for treating a human patient withtrichotillomania, the method comprising a step of local administrationof about 5 units to about 10 units of botulinum toxin type A to a headmuscle, including a frontalis muscle and an occipitalis muscle of thepatient with trichotillomania, thereby alleviating the trichotillomaniaof said patient.
 17. The method of claim 16, wherein about 5 units ofbotulinum toxin type A is additionally administered to an additionalsite on the patient's scalp.
 18. The method of claim 17, wherein thebotulinum toxin type A is administered to about 20 additional sites onthe patient's scalp.